Project Summary Bisphenol A (BPA) and phthalates are plasticizers used in the manufacturing of many household and personal care products (e.g., BPA is used in the coating of the inside surface of metal cans). These compounds can have estrogenic and inflammatory properties that could increase the risk of breast cancer. Breast density is one of the strongest risk factors for breast cancer. In a recent study, high circulating levels of BPA and monoethyl phthalate (MEP) were significantly associated with higher levels of mammographic breast density. For both compounds, breast density was about five percentage points higher among women with serum levels above the median detectable level compared with women with undetectable levels. A comparable percentage- point difference in breast density has been linked with a 5 to 10% increase in breast cancer risk in other epidemiologic studies. Concerns about the serum assay used in the BPA/phthalate-breast density study and the single time-point exposure measurement have led to controversy over its findings although it is not clear how a spurious positive association could have emerged. Further research is clearly needed to verify the findings, especially since the underlying mechanism is not understood. The fact that high MEP urinary levels were also associated with a four-fold increased risk of breast cancer in premenopausal women in a case- control study conducted in Mexico, and that a recent case-control study conducted in Canada observed striking associations between breast cancer risk in premenopausal women and employment in plastics manufacturing and in food canning further underscore the need for research in this area. We hypothesize that high exposure to BPA and some phthalates results in increased inflammation in the breast microenvironment that contributes to increased breast density and breast cancer susceptibility. In an innovative study approach, we will examine the relation between urinary and milk levels of BPA/phthalate metabolites, inflammatory markers in the breast, and breast density in 250 nursing first time mothers. Urinary levels of BPA and 12 phthalate metabolites will be measured at two time points: six weeks after birth [T0] and six months after cessation of breastfeeding [T1]. Breast milk levels of BPA and key breast inflammatory markers will also be measured at T0. Non-enhanced magnetic resonance imaging (MRI) will be used to assess percent dense volume at T1. The unique strengths of this study are the multiple time-point exposure measurements, the selection of accepted matrices to measure these chemicals, the ability to examine the potential inflammatory effects of these chemicals directly in the breast microenvironment, and the opportunity to examine risk in a diverse population of young women.